title: Inhibition of phosphatidylinositol 3-kinase/Akt signaling attenuates hypoxia-induced pulmonary artery remodeling and suppresses CREB depletion in arterial smooth muscle cells.
abstract: Hypoxia-induced pulmonary hypertension is characterized by progressive remodeling of the pulmonary artery (PA) system and loss of the transcription factor, cAMP response element binding protein (CREB) in PA smooth muscle cells (SMCs). Previous in vitro studies suggested that platelet-derived growth factor, a mitogen produced in the hypoxic arterial wall, elicits loss of CREB in medial SMCs via the PI3K/Akt pathway. These events trigger switching of SMCs from a quiescent, contractile phenotype to a proliferative, migratory, dedifferentiated, and synthetic phenotype, which contributes to PA thickening. Here, we investigated whether inhibition of PI3K or Akt could attenuate arterial remodeling in the lung and prevent CREB loss in PA medial SMCs in rats subjected to chronic hypoxia. Inhibition of either enzyme-blunted hypoxia-induced PA remodeling and SMC CREB depletion and diminished SMC proliferation and collagen deposition. Inhibition of Akt, but not PI3K, suppressed muscularization of distal arterioles and blunted right ventricular hypertrophy. Interestingly, mean PA pressure was elevated equally by hypoxia in untreated and inhibitor-treated groups but was normalized acutely by the Rho kinase inhibitor, Fasudil. We conclude that PI3K and Akt inhibitors can attenuate hypoxia-induced PA remodeling and SMC CREB depletion but fail to block the development of pulmonary hypertension because of their inability to repress Rho kinase-mediated vasoconstriction.
authors.affiliation: *Cardiovascular Pulmonary Research Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO; Divisions of †Pulmonary Science and Critical Care Medicine; and ‡Endocrinology; University of Colorado Anschutz Medical campus, Aurora, CO; and §Research and Endocrine Services, Veterans Affairs Medical Center, Denver, CO.
authors.forename: Chrystelle V
authors.initials: CV
authors.lastname: Garat
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Crossno
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Sullivan
authors.forename: Jane E B
authors.initials: JE
authors.lastname: Reusch
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Klemm
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000819:agonists* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000517:prevention & control; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D055550:Protein Stability / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; D058539:Phosphatidylinositol 3-Kinase; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases